Recent evidence indicates that, although the primary site of action of the anticancer drug, methylglyoxal-bis(guanylhydrazone), probably involves mitochondria, the basis for its cytotoxicity and tissue selectivity is highly dependent on its uptake characteristics. In particular, the drug utilizes the facilitated transport mechanism of spermidine to gain entry into cells where it is concentrated by as much as 1000-fold. The example of MGBG suggests that spermidine derivatives might serve as vectors to deliver biologically active moieties to neoplastic tissues and to concentrate them there intracellularly provided that the uptake characteristics of the spermidine molecule are retained. Dr. R. J. Bergeron (University of Florida) will design and synthesize a number of polyamine derivatives in order to more precisely define the structural limitations imposed by the spermidine receptor on substrate uptake. Based on these findings, a variety of N4-spermidine derivatives will be synthesized as potential anticancer agents. In addition, known antineoplastic agents will be condensed with the secondary nitrogen of spermidine in an attempt to improve their efficacy. The above compounds will be studied for their ability to inhibit tumor growth in vitro and in vivo, to interfere with polyamine uptake, to interact with DNA and to substitute for authentic polyamines in biological function(s). Most of the basic in vitro work will be performed with murine L1210 leukemia L1210 cells. Among the parameters that will be examined in assessing drug effects are cell growth and cytotoxicity, antagonism studies with Alpha-difluoro-methylornithine, competition for spermidine uptake, polyamine pool sizes, ornithine and S-adenosylmethionine decarboxylase assays, cell ultrastructure and precursor incorporation. Biologically-active compounds will be radiolabeled, by Dr. Bergeron, for the purpose of uptake and distribution studies. These studies are proposed with the ultimate goal of producing a family of polyamine derivatives having usefulness as anticancer agents and/or as experimental probes for studying the cellular function(s) and uptake characteristics of polyamines in neoplastic tissues.